Tuesday, May 1, 2012

Fighting Cancer on Her Turf: Deoxynyboquinone

This past July, one of my peers at the Stritch School of Medicine’s Summer Enrichment Program introduced me to his research with DNQ. I learned that DNQ is short for “deoxynyboquinone,” a potential anticancer agent which is depicted in the figure above. (Ace Website) During the program, a lecture given by an oncologist furthered my interest in cancer research and in the medical specialty of oncology. I was intrigued to revisit the topic of DNQ on my own time. I thought, "How exactly does DNQ fight cancer? How long has it been studied for?" I began searching for information online regarding DNQ this semester, and I found that I was continually led to an article from my home institution, the University of Illinois at Urbana-Champaign. The article was titled “Chemistry and biology of deoxynyboquinone, a potent inducer of cancer cell death.” (Bair, et al). The research group synthesized DNQ in a series of steps and determined how it promotes cancer cell death. The abstract said that “Experiments performed on cancer cells grown in hypoxia and normoxia strongly suggest that DNQ undergoes bioreduction to its semiquinone, which then is re-oxidized by molecular oxygen, forming superoxide that induces cell death.” I was unfamiliar with the terms normoxia and hypoxia, as well as semiquinone. Knowing that these would be important in order to understand the group’s work, I decided to make those terms part of my initial information search. One definition of semiquinone is “any class of free radicals formed as intermediates in the oxidation of a hydroquinone to a quinone.” (dictionary.com) Additionally, I found that normoxic conditions are environments with normal oxygen levels, and hypoxic conditions are oxygen deficient. (Medical Dictionary) After clarifying these words, I was able to focus on more essential questions. For instance, what did DNQ have to do with these two particular environments? The U of I article included the figure below, which depicts the effect of DNQ on cervical cancer cells in normoxic conditions and in hypoxic conditions.

The graph shows DNQ’s dose dependence for inducing cell death under each of these conditions. This raised another question for me: How do these results with DNQ compare to those of other experimental anti-cancer agents? Can all potential agents work in both conditions? The researchers stated that DNQ is “the most potent anti-neoplastic agent that operates predominantly through this direct ROS generation, bioreduction mechanism.” I read on. Unlike the experimental therapeutic elesclomol, DNQ is able to induce cancer cell death under hypoxic conditions. Elesclomol can only induce such death in normoxic conditions, conditions of ample oxygen. I wondered: is it beneficial that DNQ can function in both? Yes, as this allows DNQ to “fight cancer on her turf.” For example, tumors tend to have hypoxic conditions in the interior. DNQ can work in that environment. Since DNQ can induce cancer cell death in both of these conditions, it is effective in handling more tumors than anticancer agents that are specific to one or the other. Once I had a better understanding of DNQ’s ability to work in typical tumor environments, I wanted to learn more about its mechanistic actions. I wondered, "What does it actually do?"

Another article by University of Illinois researchers provided me with such information. The article discusses “reactive oxygen species” (ROS), chemically reactive molecules containing oxygen. (Genetics) The article indicates that there are increased levels of ROS in cancer cells because of increased metabolism, among other things. The authors proposed that perhaps disrupting the ROS levels in cancer cells could serve as an anticancer strategy. The authors stated that inhibition of this stress response or directly generating reactive oxygen species can be useful outcomes of anti-cancer drugs. I did not fully understand how ROS could aid in killing cancer cells because I had previously studied in a Molecular and Cellular Biology course that ROS promote cell mutation and proliferation. Later in the article, however, the authors explained that cancer cells have higher oxidative stress levels, yet are also more sensitive to increases in oxidative stress. Increasing the ROS to a level sufficient to kill cancer cells would be helpful, as long as it is within the antioxidant capacity of healthy cells. I began to synthesize what I read with what I had learned about DNQ. I came to the conclusion that in the case of DNQ, increasing the level is beneficial in that it induces the oxidative stress response. (Hergenrother and Parkinson) Another article explained that DNQ does not act alone in raising ROS levels. NQO1, an enzyme over-expressed in most solid tumors, is involved. DNQ generates toxic levels of ROS selectively in cancer cells through a bioreduction/ oxidation process which is mediated exclusively by this enzyme.

One might wonder why DNQ is not being used widely today as an anticancer strategy in humans if research supports DNQ's potential as a novel anticancer agent. After reading additional articles, I came across an explanation. While there have been studies with rats indicating that DNQ reduces the size of tumors in these rodents, it would be unsuccessful in humans. This is because DNQ has a poor aqueous solubility, which requires the use of a formulation with a high concentration of 2-hydroxypropyl-Beta-cyclodextrin (HPBCD), which is shown below to the right.

This would complicate human treatment. However, the researchers did not give up. They knew they could find a better option for humans---a more soluble, yet equipotent derivative of DNQ. (Bair and Hergenrother). The authors explained that a subset of derivatives have been found that are equipotent to DNQ and as much as 4-fold more soluble in water, 250-fold more soluble in organic solvents, and 9-fold more soluble in an aqueous solution of HPBCD. Moreover, studies have shown that mice can tolerate as much as 4-fold more of the best of these derivatives than they could DNQ. For now, research and extensive human trials must be carried out to determine if these will be successful anticancer agents as predicted.

Overall, the articles I read answered my question as to how DNQ serves to induce cell death; its mechanism involves reactive oxygen species. DNQ generates toxic levels of ROS selectively in cancer cells through a bioreduction/oxidation process mediated by NQO1. Although DNQ reduces the size of tumors in a mouse, it is not used in humans because HPBCD (which is added due to DNQ's poor aqueous solubility) complicates treatment. Instead, the future will be comprised of identifying DNQ derivatives which are more soluble yet equipotent, testing these derivatives in human clinical studies, and implementing them as an anticancer strategy once deemed safe. In researching DNQ, I have acquired foundational knowledge that I can build upon as research on DNQ derivatives progresses. Below is a "Jmol image" of DNQ, and the buttons can be utilized to view either a rotating or stationary image.

Finally, as a premedical student, researching DNQ and its role in both organic chemistry and medicine has helped me to understand why organic chemistry is a required course for students with this professional goal; it has important implications in oncology and all fields of
medicine. The articles I read
on DNQ highlighted the fact that the most extreme, elevated levels of reactive oxygen
species are characteristic of pancreatic cancer and other cancers that are
unresponsive to drugs. While I
know organic chemistry I and II are important for the Medical College Admissions
Test and medical school, it was not until after making this application of the
material to a topic of interest to me that I truly grasped its relevance outside of
that scope. Practicing medicine is
my ultimate ambition, and seeing the importance of organic chemistry in
understanding anticancer agents and drug mechanisms makes my current enrollment
in organic chemistry II seem worthwhile.
If students take the time to apply course material to their
passions and interests outside of class, it can make learning the material
easier and more effective.

3 comments:

I really liked your blog topic. Cancer is relevant to everyone's life whether it be personally or through someone we know. Finding a cure is a common goal everyone shares so this topic fits all audiences. I also liked how you defined the words you did not know, it made the rest of the blog easier to understand. I was also unaware that ROS could serve any sort of beneficial purpose,so that was something I learned by reading your blog.

I enjoyed reading your blog about DNQ and how it kills cancer cells. I liked how you were able to break it down into: what it is, how it works, why it isn't on the market for humans, and how they are trying to fix it. It was interesting to learn that a drug that looks to work really well in theory doesn't quite work in the real world and the steps that are being done to improve it.

I very much enjoyed the writing style and flow of your article. Your inquiry into DNQ started out simply enough but quickly developed into a more detailed pursuit of the functions of the molecule. I really enjoyed the context in which you introduced how you came up with your title. It makes the reader stop and think about why DNQ is so important compared to other anti-cancer treatments. Great job!